1-Imidazolidinyl-phenyls

ABSTRACT

A particular subject of the invention is the products of formula (I): ##STR1## in which: R 1  and R 2  represent in particular cyano and trifluoromethyl, 
     R 3  represents in particular alkyl, alkenyl or alkynyl, optionally substituted by one or more halogen, cyano or hydroxyl radicals, 
     R 4  and R 5  either represent in particular methyl optionally substituted by fluorine, 
     or form in particular a cyclohexyl radical, 
     X and Y represent in particular oxygen, 
     as well as their salts and isomers.

This application is a 371 PCT/FR96/01846 filed Nov. 21, 1996.

The present invention relates to new fluorinated or hydroxylatedphenylimidazolidines, their preparation process, the new intermediatesobtained, their use as medicaments, their new use and the pharmaceuticalcompositions containing them.

A subject of the present invention is the products of formula (I):##STR2## in which: R₁ and R₂, identical or different, are chosen fromcyano, nitro, trifluoromethyl radicals and halogen atoms,

R₃ represents a linear or branched aryl, arylalkyl, alkyl, alkenyl oralkynyl radical containing at most 10 carbon atoms and optionallysubstituted by one or more radicals chosen from halogen atoms and cyano,hydroxyl, alkoxy, carboxy, acyl and acyloxy radicals, in which, ifappropriate, the alkyl, alkoxy and acyl radicals are linear or branched,containing at most 10 carbon atoms, the carboxy radical is free,salified, esterified or amidified and the hydroxy radical is free,esterified, etherified or protected,

R₄ and R₅ identical or different, represent a linear or branched alkylradical containing at most 4 carbon atoms and optionally substituted bya halogen atom, or form with the carbon atom to which they are linked acyclic radical constituted by 3 to 7 members and optionally containingone or more identical or different heteroatoms, chosen from oxygen,sulphur or nitrogen atoms,

X and Y, identical or different, represent an oxygen or sulphur atom,

said products of formula (I) being in all the possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

In the products of formula (I) and in what follows:

the term halogen designates fluorine, chlorine, bromine or iodine atoms,

The fluorine, chlorine or bromine atoms are preferred.

The term linear or branched alkyl radical designates the followingradicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl,nonyl and decyl, as well as their linear or branched position isomers,

Alkyl radicals having at most 6 carbon atoms are preferred and inparticular the methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl andn-hexyl radicals.

The term linear or branched alkenyl radical designates the vinyl, allyl,1-propenyl, butenyl, 1-butenyl, pentenyl or hexenyl radicals as well astheir linear or branched position isomers.

Among the alkenyl radicals, the vinyl, allyl, n-butenyl or isobutenylvalues are preferred.

The term alkynyl designates a linear or branched radical having at most12 carbon atoms such as for example ethynyl, propargyl, butynyl,pentynyl or hexynyl.

Among the alkynyl radicals, those with 4 carbon atoms are preferred andin particular the propargyl radical.

The term linear or branched alkoxy radical designates the methoxy,ethoxy, propoxy, isopropoxy, Linear, secondary or tertiary butoxy,pentoxy or hexoxy radicals as well as their linear or branched positionisomers.

The term cyclic radical constituted by 3 to 7 members and optionallycontaining one or more identical or different heteroatoms, chosen fromoxygen, sulphur or nitrogen atoms, designates on the one hand acycloalkyl radical which itself designates in particular the cyclobutyl,cyclopentyl and cyclohexyl radicals and on the other hand a carbocyclicradical interrupted by one or more heteroatoms chosen from oxygen,nitrogen or sulphur atoms such as quite particularly the saturatedmonocyclic heterocyclic radicals such as for example the followingradicals: oxetannyl, oxolannyl, dioxanyl, dithiolane, thiooxolane,thiooxane, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, azetidine,oxetane and thietane.

The term acyl radical preferably designates the formyl, acetyl,propionyl, butyryl and benzoyl radicals, but also the valeryl, hexanoyl,acryloyl, crotonoyl and carbamoyl radicals.

The term acyloxy radical designates the radicals in which the acylradicals have the meaning indicated above and for example the acetoxy orpropionyloxy radicals.

The term aryl designates the carbocyclic aryl radicals such as phenyl ornaphthyl and the heterocyclic monocyclic aryl radicals with 5 or 6members or constituted by condensed rings, containing one or moreheteroatoms preferably chosen from oxygen, sulphur and nitrogen. Amongthe heterocyclic aryl radicals with 5 members the following radicals canbe mentioned: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl,thiadiazolyl, pyrazolyl, isoxazolyl, tetrazolyl.

Among the heterocyclic aryl radicals with 6 members, the pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl radicals can be mentioned.

Among the condensed aryl radicals, the indolyl, benzofuranyl,benzothienyl, quinolinyl radicals can be mentioned.

The phenyl, tetrazolyl and pyridyl radicals are preferred.

The term arylalkyl designates the radicals resulting from thecombination of the alkyl radicals and the aryl radicals mentioned above.

The benzyl, phenylethyl, pyridylmethyl, pyridylethyl or tetrazolylmethylradicals are preferred.

As particular examples of alkyl radicals substituted by one or morehalogens, the monofluoro-, chloro- or bromo- methyl, difluoro-,dichloro- or dibromo-methyl and trifluoromethyl radicals can bementioned.

The carboxy radical or radicals of the products of formula (I) can befree, salified, esterified or amidified by the various groups known to aman skilled in the art.

There can be mentioned, for example:

the carboxy radicals salified by mineral bases such as, for example, anequivalent of sodium, potassium, lithium, calcium, magnesium or ammoniumor organic bases such as, for example, methylamine, propylamine,trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine,tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline,dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine,histidine, N-methylglucamine.

The sodium or potassium salts are preferred.

the carboxy radicals esterified by alkyl radicals in order to formalkoxy carbonyl groups such as, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxy-, isobutoxy- andtert-butoxy-carbonyl or benzyloxycarbonyl, these alkyl radicals beingable to be substituted by radicals chosen for example from halogenatoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or arylradicals such as, for example, in the chloromethyl, hydroxypropyl,methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl,benzyl or phenethyl groups.

The radicals formed with the easily cleavable ester remainders can alsobe mentioned, such as the methoxymethyl, ethoxymethyl radicals; theacyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl,acetoxymethyl or acetoxyethyl; the alkyloxycarbonyloxy alkyl radicalssuch as the methoxycarbonyloxy methyl or ethyl radicals, theisopropyloxycarbonyloxy methyl or ethyl radicals.

A list of such ester radicals can be found for example in the EuropeanPatent EP 0,034,536.

By amidified carboxy is meant the groups of --CON(R₆)(R₇) type in whichthe R₆ and R₇ radical identical or different represent a hydrogen atomor an alkyl radical having 1 to 4 carbon atoms such as the followingradicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butylor tert-butyl.

Among the --CON(R₆)(R₇) groups defined above, those in which the--N(R₆)(R₇) represents the amino, mono- or dimethylamino radical arepreferred.

The N(R₆)(R₇) radical can also represent a heterocycle which may or maynot contain an additional heteroatom. The pyrrolyl, imidazolyl, indolyl,piperidino, morpholino, piperazinyl radicals can be mentioned. Thepiperidino or morpholino radicals are preferred.

By esterified, etherified or protected hydroxyl radical is meant the##STR3## radicals respectively, formed from an --OH hydroxyl radical,according to the usual methods known to a man skilled in the art and inwhich P represents a protective group, α₁, α₂ and α₃ represent inparticular an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical, havingat most 12 carbon atoms and optionally substituted as is defined abovein particular for R₃.

Examples of the protective group P, as well as the formation of theprotected hydroxyl radical, are given in particular in the usual book ofa man skilled in the art: Protective Groups in Organic Synthesis,Theodora W. Greene, Harvard University, printed in 1981 byWiley-Interscience Publishers, John Wiley & Sons.

The protective group of the hydroxyl radical which can be represented byP, can be chosen from the list below: for example formyl, acetyl,chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl,p-nitrobenzoyl. The following groups can also be mentioned:ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl,βββ-trichloroethoxy-carbonyl, benzyloxycarbonyl, tertbutoxycarbonyl,1-cyclo propylethoxycarbonyl, tetrahydropyrannyl,tetrahydrothio-pyrannyl, methoxytetrahydropyrannyl, trityl, benzyl,4-methoxybenzyl, benzhydryl, trichloroethyl, 1-methyl 1-methoxyethyl,phthaloyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl,succinyl and pivaloyl, phenylacetyl, phenylpropionyl, mesyl,chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, caprylyl,acryloyl, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl.

P can in particular represent the radical ##STR4## or also a siliconderivative such as trimethylsilyl.

The addition salts with mineral or organic acids of the products offormula (I) can be, for example, the salts formed with the followingacids: hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric,phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric,succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic,alkylmonosulphonic such as for example methanesulphonic,ethanesulphonic, propanesulphonic, alkyldisulphonic such as for examplemethanedisulphonic, alpha, beta-ethanedisulphonic, arylmonosulphonicsuch as benzenesulphonic and aryldisulphonic.

There can be mentioned more particularly the salts formed with thehydrochloric or methanesulphonic acids for example.

It can be remembered that stereoisomerism can be defined as theisomerism of compounds having the same developed formulae, but thevarious groups of which are arranged differently in space, such as inparticular in the boat and chair shapes of cyclohexane andmono-substituted cyclohexanes whose substituent can be in axial orequatorial position, and the various possible rotational conformationsof ethane derivatives. However, another type of stereoisomerism exists,due to the different spatial arrangements of fixed substituents, eitheron double bonds, or on rings, which is often called geometricalisomerism or cis-trans isomerism. The term stereoisomeric is used in thepresent Application in its broadest sense and therefore relates to allof the compounds indicated above.

In the products of formula (I) and in what follows, it can be notedthat:

the hydrogen atoms which are contained by the optionally substitutedalkyl or alkenyl radicals which can be represented by R₃ can bedeuterium atoms,

the fluorine atoms which can be represented by halogen atoms can be an¹⁸ F atom which is useful for medical imagery.

Thus a subject of the present invention is the products of formula (I)as defined above, in which: R₁ and R₂ both represent a chlorine atom, orbeing identical or different are chosen from the cyano, nitro andtrifluoromethyl radical,

R₃ represents a linear or branched phenyl, pyridyl, phenylalkyl,pyridylalkyl, alkyl, alkenyl or alkynyl radical containing at most 4carbon atoms and optionally substituted by one or more radicals chosenfrom halogen atoms and cyano, hydroxyl, alkoxy, acyl and acyloxyradicals, in which if appropriate, the acyl and alkoxy radicals arelinear or branched, containing at most 6 carbon atoms and the hydroxylradical is free, esterified or protected,

R₄ and R₅, identical or different, represent a methyl radical optionallysubstituted by a halogen atom, or form with the carbon atom to whichthey are linked a cyclobutyl, cyclopentyl, cyclohexyl, dioxane radical,or a ##STR5## radical in which W represents an oxygen or sulphur atom orthe --NH radical,

X and Y, identical or different, represent an oxygen or sulphur atom,

said products of formula (I) being in all the possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

The ##STR6## radical represents in particular the piperidyl ortetrahydropyran radical.

A particular subject of the present invention is the products of formula(I) as defined above, in which:

R₁ and R₂ represent a cyano radical and a trifluoromethyl radical,

R₃ represents a linear or branched alkyl, alkenyl or alkynyl radical,containing at most 4 carbon atoms and optionally substituted by one ormore radicals chosen from halogen atoms, the cyano radical and the free,esterified or protected hydroxyl radical,

R₄ and R₅, identical or different, represent a methyl radical optionallysubstituted by a fluorine atom, or form with the carbon atom to whichthey are attached a cyclohexyl radical

X and Y represent an oxygen atom, said products of formula (I) being inall the possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as the addition salts with mineral and organic acids orwith mineral and organic bases of said products of formula (I).

Among the preferred products of the invention, there can be mentionedmore particularly the products of formula (I) as defined above the namesof which follow:

4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(2-fluoroethyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-(2,5-dioxo-4,4-bis(fluoromethyl)-3-ethyl-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(4-hydroxy-2-butyn-1-yl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-(3-(4-hydroxy-2-butyn-1-yl)-4,4-dimethyl-2,5-dione-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-[2,4-dioxo-1-(4-hydroxybutyl)-1,3-diazaspiro[4.5]decan-3-yl]-2-(trifluoromethyl)-benzonitrile,said products of formula (I) being in all the possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

Also a subject of the present invention is a preparation process for theproducts of formula (I), as defined above, characterized in that, in thepresence of a tertiary base, a product of formula (II): ##STR7## inwhich R'₁ and R'₂ have the meanings indicated above, for R₁ and R₂respectively, in which the optional reactive functions are optionallyprotected and X has the meaning indicated above, is reacted with aproduct of formula (III): ##STR8## in which R'₃, R'₄ and R'₅ have themeanings indicated above, for R₃, R₄ and R₅ respectively in which theoptional reactive functions are optionally protected, in order to obtaina product of formula (IV): ##STR9## in which X, R'₁, R'₂, R'₃, R'₄ andR'₅ have the meanings indicated above,

which is converted into a product of formula (V): ##STR10## in which X,R'₁, R'₂, R'₃, R'₄ and R'₅ have the meanings indicated above,

which products of formulae (IV) and (V), if necessary or if desired, inorder to obtain products of formula (I) as defined above, can besubjected to any one or more of the following reactions, in any order:

a) if appropriate conversion of the >C═S group which can be representedby >C═X in the >C═O group,

b) the action on the products of formula (V) in which R'₃ represents ahydrogen atom, of a reagent of formula Hal-R"₃ in which R"₃ has thevalues indicated above for R₃, with the exception of the hydrogen value,and in which the optional reactive functions are optionally protected,and Hal represents a halogen atom, in order to obtain the correspondingproducts, in which R'₃ is replaced by R"₃,

c) release of the OH radical which can be carried by one or both of R'₄and R'₅ and/or R'₃,

d) esterification or conversion of the OH radical into ahalogen radical,

e) elimination reaction of the optional protective groups,

f) if appropriate the action of an esterification, amidification orsalification agent,

g) resolution reaction of the racemic forms, said products of formula(I) thus obtained being in all the possible racemic, enantiomeric anddiastereoisomeric isomer forms.

The action of the products of formula (II) with the products of formula(III) in order to obtain the products of formula (IV) can be carried outin an organic solvent such as tetrahydrofuran or dichloroethane butethyl ether or isopropyl ether can also be used.

The operation is carried out in the presence of a tertiary base such astriethylamine or also pyridine or methylethylpyridine.

The optional reactive functions which are optionally protected can be inparticular the hydroxy or amino functions. The usual protective groupsare used to protect these functions. The following protective groups ofthe amino radical can for example be mentioned: tert-butyl, tertamyl,trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl,benzyloxycarbonyl, terbutyloxycarbonyl.

As the protective group of the hydroxy radical there can be mentionedfor example the tetrahydropyrannyl, trimethylsilyl, triphenylmethyl ortert-butyl dimethylsilyl radicals.

Of course the above list is not limitative and other protective groups,for example known in the chemistry of the peptides, can be used. A listof such protective groups is found for example in the French Patent BF2,499,995 whose content is incorporated here by reference.

In the product of formula (III), R₄ and R₅ can form a cyclic radicalwith the carbon atom that carries them, such as in particular acyclohexyl radical.

Also, in the product of formula (III), one or both of R₄ and R₅ may ormay not carry a hydroxyl radical which can be protected in particular asan -O-tetrahydropyrannyl (OTHP).

The reaction of the product of formula (II) as defined above with aproduct of formula (III) as defined above in order to produce thecorresponding product of formula (IV), can then be carried out inparticular in the presence of methylene chloride at a temperature ofabout -30° C.

The optional elimination reactions of the protective groups are carriedout according to the usual methods known to a man skilled in the art or,for example, as indicated in the Patent BF 2,499,995. The preferredmethod of elimination is acid hydrolysis using acids chosen fromhydrochloric, benzene sulphonic or paratoluene sulphonic, formic ortrifluoroacetic acids. Hydrochloric acid is preferred.

The optional hydrolysis reaction of the >C═NH group into the carbonylgroup in order to convert in particular the product of formula (IV) intothe product of formula (V) is preferably carried out using an acid suchas aqueous hydrochloric acid, for example under reflux.

The action on the products of formula (V) of the reagent of formulaHal-R"₃ is carried out in the presence of a strong base such as sodiumor potassium hydride. The operation can be carried out by phase transferreaction in the presence of quaternary ammonium salts such as tetrabutylammonium dihydrogen phosphate salts.

The conversion of the OH radical into the halogen radical can be carriedout under the usual conditions known to a man skilled in the art such asin particular in a solvent such as for example tetrahydrofuran and bythe action of a halogenated derivative such as in particular, when thehalogen atom is a fluorine atom, diethylaminosulphide trifluoride(DAST).

Triflic anhydride can also be reacted beforehand in order to obtain thecorresponding triflate which is then exchanged with the correspondingfluoride as described hereafter in the examples and in particular by theaction of tetrabutylammonium fluoride.

When the halogen atom is a bromine, chlorine or iodine atom, the actioncan be carried out according to the usual conditions known to a manskilled in the art such as in particular by the action, in the presenceof triphenylphosphine, of the corresponding halogenating agent such asfor example carbon tetrabromide, carbon tetrachloride or also iodine.

The optional esterification of the products of formula (IV), (V) or (I)as defined above, which contain one or more free OH radicals is carriedout under standard conditions. For example an acid or a functionalderivative can be used, for example an anhydride such as aceticanhydride in the presence of a base such as pyridine.

The optional esterification or salification of the products of formula(IV), (V) or (I) as defined above, which contain one or more COOHgroups, is carried out under standard conditions known to a man skilledin the art.

The optional amidification of the products of formula (IV), (V) or (I)as defined above, which contain a COOH radical, is carried out understandard conditions. A primary or secondary amine can be used on afunctional derivative of the acid, for example a symmetrical or mixedanhydride.

Also a subject of the present invention is a preparation process for theproducts of formula (I'): ##STR11## in which X, Y, R'₁, R'₂, R'₃, R'₄and R'₅ are as defined above, process characterized in that a product offormula ##STR12## in which R'₁ and R'₂ have the previous meanings andHal represents a halogen atom, is reacted with a product of formula(VI): ##STR13## in which X, Y, R'₃, R'₄ and R'₅ have the meaningsindicated above, the reaction being carried out in the presence of acatalyst and optionally of a solvent.

With regard to the products of formula (VI), the term Hal preferablydesignates the chlorine atom, but can also represent a bromine or iodineatom.

The reaction conditions of such a process are in particular thosedescribed in EP 0,494,819.

The products which are a subject of the present invention possess usefulpharmacological properties, in particular they fix themselves on theandrogen receptor and they have an anti-androgenic activity.

Tests given in the experimental part illustrate these properties.

These properties make the products of formula (I) as defined above ofthe present invention of use as medicaments mainly for:

the treatment of adenomas and neoplasias of the prostate as well asbenign hypertrophy of the prostate, on its own or combined withanalogues of LHRH. They can also be used in the treatment of benign ormalignant tumours possessing androgen receptors and more particularlycancers of the breast, the skin, the ovaries, the bladder, the lymphaticsystem, the kidneys and the liver,

the treatment of cutaneous affections such as acne, hyperseborrhea,alopecia or hirsutism. These products can therefore be used indermatology on their own or combined with antibiotics such asderivatives of azelaic and fusidic acids, erythromycin, as well asderivatives of retinoic acid or an inhibitor of Salpha-reductase such as(5alpha,17beta)-1,1-dimethylethyl 3-oxo 4-aza-androst-1-ene17-carboxamide (or Finasteride, Merck 11th Ed.) for the treatment ofacne, alopecia or hirsutism. They can also be combined with a productstimulating hair growth such as Minoxidil for the treatment of alopecia.

The products of formula (I), as defined above, in radioactive form(tritium, carbon 14, iodine 125 or fluorine 18) can also be used asspecific labels for the androgen receptors. They can also be used indiagnostics for medical imagery.

The products of formula (I) as defined above can also be used in theveterinary domain for the treatment of behavioural disorders such asaggressiveness, androgen-dependent affections, such as circum analum indogs and tumours having androgen receptors. They can also be used tobring about a chemical castration in animals.

Therefore a subject of the invention is the use, as medicaments, of theproducts of formula (I) as defined above, said products of formula (I)being in all the possible racemic or optically-active isomer forms, aswell as the addition salts with pharmaceutically acceptable mineral ororganic acids or mineral and organic bases of said products of formula(I).

A particular subject of the invention is the use, as medicaments of theproducts of formula (I) as defined above, in which:

R₁ and R₂ represent a cyano radical and a trifluoromethyl radical,

R₃ represents a linear or branched alkyl, alkenyl or alkynyl radical,containing at most 4 carbon atoms and optionally substituted by one ormore radicals chosen from halogen atoms, the cyano radical and the free,salified or protected hydroxyl radical,

R₄ and R₅ are either identical or different and represent a methylradical optionally substituted by a fluorine atom, or form with thecarbon atom to which they are attached a cyclohexyl radical,

X and Y represent an oxygen atom, said products of formula (I) being inall the possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as the addition salts with pharmaceutically acceptablemineral and organic acids or mineral and organic bases of said productsof formula (I).

Also a subject of the invention is the use, as medicaments, of thefollowing products:

4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(2-fluoroethyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-(2,5-dioxo-4,4-bis(fluoromethyl)-3-ethyl-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(4-hydroxy-2-butyn-1-yl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-(3-(4-hydroxy-2-butyn-1-yl)-4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,

4-[2,4-dioxo-1-(4-hydroxybutyl)-1,3-diazaspiro[4.5]decan-3-yl]-2-(trifluoromethyl)-benzonitrile,said products of formula (I) being in all the possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with pharmaceutically acceptable mineral and organic acids ormineral and organic bases of said products of formula (I).

The products can be administered by parenteral, buccal, perlingual,rectal or topical route.

Also a subject of the invention is the pharmaceutical compositions,characterized in that they contain, as active ingredient, at least oneof the medicaments of formula (I), as defined above.

These compositions can be presented in the form of injectable solutionsor suspensions, tablets, coated tablets, capsules, syrups,suppositories, creams, ointments and lotions. These pharmaceutical formsare prepared according to the usual methods. The active ingredient canbe incorporated with excipients usually employed in these compositions,such as aqueous or non-aqueous vehicles, talc, gum arabic, lactose,starch, magnesium stearate, cocoa butter, fatty substances of animal orvegetable origin, paraffin derivatives, glycols, various wetting,dispersing or emulsifying agents, preservatives.

The usual dose, variable according to the patient treated and theaffection in question, can be, for example, from 10 mg to 500 mg per dayin man, by oral route.

The products of formula (II) used at the start of the invention can beobtained by the action of phosgene when X represents an oxygen atom orthiophosgene when X represents a sulphur atom on the corresponding amineof formula (A): ##STR14## in which R'₁ and R'₂ have the meaningsindicated above.

A product of this type is in particular described in the French PatentBF 2,329,276.

Amines of formula (A) are described in the European Patent EP 0,002,892or the French Patent BF 2,142,804. The products of formula (III) areknown or can be prepared from the corresponding cyanohydrin according tothe process described in the publications: J. Am. Chem. Soc. (1953), 75,4841, BEIL I 4 526 or J. Org. Chem. 27 2901 (1962).

The products of formula (III) in which R'₃ is different from a hydrogenatom can be obtained by the action of a product of formula R"₃ Hal on2-cyano 2-amino propane under the conditions stated above for the actionof R"₃ Hal on the products of formula (V). An example of this type ofpreparation is described in the reference:

Jilek et al. Collect. Czech. Chem. Comm. 54(8) 2248 (1989).

The products of formulae (VII) and (VI), used at the start of theprocess indicated above, for obtaining products of formula (I), asdefined above, are known and commercially available or can be preparedaccording to methods known to a man skilled in the art.

The preparation of products of formula (VI) is described in particularin the following publications:

Zhur. Preklad. Khim. 28, 969-75 (1955) (CA 50, 4881a, 1956)

Tetrahedron 43, 1753 (1987)

J. Org. Chem. 52, 2407 (1987)

Zh. Org. Khim. 21, 2006 (1985)

J. Fluor. Chem. 17, 345 (1981) or in the:

German Patent DRP 637,318 (1935)

European Patent EP 0,130,875

Japanese Patent JP 81,121,524.

The products of formula (VI) which are hydantoin derivatives are widelyused and mentioned in the literature such as for example in thefollowing articles:

J. Pharm. Pharmacol., 67, Vol. 19(4), p. 209-16 (1967)

Khim. Farm. Zh., 67, Vol. 1 (5) p. 51-2

German Patent 2,217,914

European Patent 0,091,596

J. Chem. Soc. Perkin. Trans. 1, p. 219-21 (1974).

Also a subject of the invention is, as new industrial products and inparticular as new industrial products which can be used as intermediateproducts for the preparation of the products of formula (I) as definedabove, the products of formulae (IV) and (V) as defined above andnotably the products of formula (V) in which R₄ and R₅ represent analkyl radical substituted by a free, esterified, etherified or protectedhydroxyl radical.

Also a subject of the present invention is the use of the products offormula (I) as defined above, for the preparation of pharmaceuticalcompositions intended for the treatment of adenomas and neoplasias ofthe prostate as well as of benign hypertrophy of the prostate, on theirown or combined with analogues of LHRH, for the treatment of cutaneousaffections such as acne, hyperseborrhea, alopecia or hirsutism or indiagnostics for medical imagery.

The following examples illustrate the invention without however limitingit.

Preparation 1 2-(trifluoromethyl) benzonitrile 4-isocyanate.

10 g of 4-cyano 3-(trifluoromethyl) aniline (described in the EuropeanPatent EP 0,002,892) in solution in 30 ml of ethyl acetate is added over20 minutes to 33.6 ml of a toluenic solution of phosgene at 1.93 M/lcooled down to 0/5° C. Agitation is carried out for 30 minutes at thistemperature then the reaction medium is left to rise to 25° C. It isheated until distillation is achieved, compensating for the volumedistilled off with toluene until the distillation temperature reaches110° C. Reflux is maintained until the release of hydrochloric acid hasstopped (i.e. 4 hours 30 minutes). The medium is returned to ambienttemperature, the insoluble part is separated out over sodium sulphateunder an inert atmosphere, followed by rinsing three times with 10 ml oftoluene and evaporating to dryness under reduced pressure. After heatingat 60° C. for one hour, the temperature is returned to ambient underinert atmosphere and 11.6 g of expected product is obtained.

ANALYSES:

    ______________________________________                                               Infra-red (cm.sup.-1)                                                  ______________________________________                                               --N═C═O                                                                         2268                                                           --CN 2233                                                                   ______________________________________                                    

EXAMPLE 14-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(2-fluoroethyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

STAGE 1: 1,3 bis [(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone

9 g of 2,5-dihydroxy-1,4-dioxane-2,5-dimethanol is introduced into 60 mlof dioxane and the suspension is taken to about 70° C. for 15 minutesthen returned to ambient temperature. 20 ml of 3,4-dihydro 2H-pyran and300 mg of monohydrated paratoluene sulphonic acid are then added and thetemperature is maintained at about 40° C. then the whole is left for 16hours at ambient temperature. The reaction medium is poured into amixture of 300 ml of saturated sodium bicarbonate solution +10 ml oftriethylamine and extraction is carried out 4 times with methylenechloride. The organic phase is washed with salt water and dried. Afterpurification by passage through silica, eluting with cyclohexane-ethylacetate: 8-2 with 0.5% of triethylamine, 17 g of expected product (paleyellow syrup) is obtained.

ANALYSES:

    ______________________________________                                               IR CHCl.sub.3 (cm.sup.-1)                                              ______________________________________                                               Absence OH                                                               O═C 1736                                                                ______________________________________                                    

STAGE 2: 2-amino-3-((tetrahydro-2H-pyran-2-yl)oxy)-2-(((tetrahydro-2H-pyran-2-yl)-oxy)-methyl)-propanenitrile.

5.6 g of the product obtained in Stage 1 above is introduced into 8 mlof ammonium hydroxide, the mixture is taken to about -5° C. and 1.58 gof ammonium chloride and 1.23 g of sodium cyanide are added successivelyand the reaction medium is left to rise to ambient temperature for about40 minutes then heated at 40° C.±5° C. under agitation overnight. It isreturned to ambient temperature and extraction is carried out 3 timeswith chloroform, the organic phase is washed with salt water and dried.After purification on silica, eluting with cyclohexane-ethyl acetate:3-7 with 0.5% of triethylamine, 4.41 g of expected product (pale yellowsyrup) is obtained.

ANALYSES:

    ______________________________________                                        IR CHCl.sub.3 (cm.sup.-1)                                                     ______________________________________                                        --CN                 2235                                                       NH.sub.2 3390-3317                                                          ______________________________________                                    

STAGE 3:4-(5-imino-2-oxo-4,4-bis(((tetrahydro-2H-pyran-2-yl)-oxy)-methyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

570 mg of the product obtained in Stage 2 above is introduced into 5 mlof isopropyl ether and 0.28 ml of triethylamine and the mixture is takento -30° C. then a solution of 12.6 ml of 1,2-dichloroethane containing2.32 g of the product obtained in Preparation 1 is added over one hour.4 ml of methylene chloride is added then the reaction medium is allowedto rise to ambient temperature, left for about 2 hours and dried. Afterpurification on silica, eluting with methylene chloride-acetone: 9-1,700 mg of expected product is obtained.

ANALYSES:

    ______________________________________                                        IR CHCl.sub.3 (cm.sup.-1)                                                     ______________________________________                                        NH                  3442-3317                                                   --CN 2235                                                                     C═O 1757                                                                  C═N 1670                                                                  Aromatic 1614-1575-1505                                                     ______________________________________                                    

STAGE 4:4-(4,4-bis(hydroxymethyl)-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

300 mg of the product obtained in Stage 3 above is introduced into 3 mlof methanol and 1.5 ml of 2N hydrochloric acid and the whole is taken toreflux for one hour 30 minutes. It is returned to ambient temperature,poured into 5 ml of bicarbonate, extraction is carried out 4 times withethyl acetate then the extracts are washed with a saturated sodiumchloride solution and dried. 5 ml of methanol is added and purificationis carried out on silica eluting with methylene chloride-methanol: 9-1.The residue is taken up in 20 ml of isopropanol under reflux thenconcentration is carried out and 225 mg of expected product (whitecrystals) is obtained. M.p.=207-208° C.

    ______________________________________                                        IR NUJOL (cm.sup.-1)                                                          ______________________________________                                        OH/NH               3525-3365-3250                                              CN 2240                                                                       C═O 1778-1738                                                             Aromatic 1618-1578-1506                                                     ______________________________________                                    

STAGE 5:4-[4,4-bis[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)-benzonitrile

331 mg of the product obtained in Stage 4 above, 4 ml oftetrahydrofuran, 1 ml of 3,4-dihydro-2H-pyran and 16 mg of p. toluenesulphonic acid, and H₂ O are introduced. After 35 minutes, the reactionmedium is poured into 10 ml of sodium bicarbonate+1 ml of triethylamineand extraction is carried out with 3×10 ml of chloroform, the extractsare washed with a saturated aqueous solution of sodium chloride, driedand evaporated to dryness. After chromatography on silica, eluting withmethylene chloride-acetone: 9-1, 500 mg of expected product (friablewhite foam) is obtained.

ANALYSES:

    ______________________________________                                        IR (CHCl.sub.3) cm.sup.-1                                                     ______________________________________                                        Absence OH,                                                                     ═C--NH 3440                                                               C.tbd.N 2236                                                                  >C═O 1791-1736                                                            Aromatics 1615-1576-1505                                                    ______________________________________                                    

STAGE 6:4-(3-(2-fluoroethyl)-4,4-bis(hydroxymethyl)-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

A) Condensation of 2-bromo-1-fluoroethane

530 mg of 50% sodium hydride is introduced and 5 g of the productobtained in Stage 5 above and 30 ml of dimethylsulphoxide dried oversiliporite are added dropwise over about 40 minutes, and rinsing iscarried out with 2 ml of dimethylsulphoxide. 20 minutes after therelease of hydrogen has stopped, 1.1 ml of 2-bromo-1-fluoroethane isadded in one lot. After reacting for 2 hours 30 minutes, the medium ispoured into 250 ml of water containing 1 g of monopotassium phosphate,extraction is carried out 4 times with ether, the organic phase iswashed with water then with salt water, dried and evaporated to dryness.Purification is carried out on silica, eluting with methylenechloride-acetone: 92.5-7.5 and in this way 5.31 g of expected product(white friable foam) is obtained.

ANALYSES:

    ______________________________________                                        IR (CHCl.sub.3) cm.sup.-1                                                     ______________________________________                                        Absence OH and NH                                                               C.tbd.N 2238                                                                  >C═O 1783-1728                                                            Aromatics 1616-1575-1505                                                    ______________________________________                                    

b) Hydrolysis of the tetrahydropyranic ethers

550 mg of the product obtained above in a) is taken up in 6 ml ofmethanol and 2 ml of hydrochloric acid (2N) and the solution obtained istaken to 40° C. for 40 minutes. It is then poured into 15 ml of asaturated solution of sodium bicarbonate, extraction is carried out 4times with ethyl acetate, the extracts are dried and evaporated todryness. Purification on silica is carried out eluting with methylenechloride-acetone: 8-2 and in this way 351 mg of expected product (whitecrystals) is obtained. M.p.=138-139° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 48.09 48.1                                                                  H  3.49  3.5                                                                  F 20.25 19.9                                                                  N 11.20 11.5                                                                ______________________________________                                        I.R. Nujol (cm.sup.-1)                                                          OH/NH 3580-3505                                                               C.tbd.N 2245                                                                  > = O 1778-1716                                                               Aromatics 1616-1580-1512                                                    ______________________________________                                    

STAGE 7:4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(2-fluoroethyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

1 ml of tetrahydrofuran is introduced, cooled down to -50° C. and 0.66ml of diethylamino trifluorosulphide is added dropwise over about oneminute, then 375 mg of the product obtained in Stage 6 above and 4 ml oftetrahydrofuran are added over 5 minutes at this temperature. Thereaction medium is rinsed with 0.5 ml of tetrahydrofuran and taken toabout 30° C. After one hour, it is poured slowly into 50 ml of asaturated solution of sodium bicarbonate+10 g of ice, extraction iscarried out 3 times with chloroform, the organic phase is washed withsalt water, dried and evaporated to dryness. Purification is carried outon silica eluting with methylene chloride-cyclohexane: 9-1 and in thisway 337 mg of expected product (white crystals) is obtained.M.p.=136-137° C. ps ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 47.50 47.5                                                                  H  2.92  2.8                                                                  F 30.06 29.9                                                                  N 11.08 11.0                                                                ______________________________________                                        IR (CHCl.sub.3) (cm.sup.-1)                                                     C.tbd.N 2295                                                                  > = O 1787-1736                                                               Aromatics 1617-1577-1505                                                    ______________________________________                                    

EXAMPLE 2 5,5-bis(fluoromethyl)-3-(4-cyano-3-(trifluoromethyl)phenyl)-2,4-dioxo-1-imidazolidineacetonitrile

STAGE 1:5,5-bis[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-3-[4-cyano-3-(trifluoromethyl)phenyl]-2,4-dioxo-1-imidazoleacetonitrile

0.504 g of sodium hydride at 50% in oil and 5 g of the product obtainedin Stage 5 of Example 1 are introduced into 40 ml of dimethylformamideon siliporite, the mixture is rinsed with dimethylformamide and after 20minutes 0.8 ml of bromoacetonitrile in 1 ml of anhydrousdimethylformamide is added. After agitation for 50 minutes, the reactionmedium is poured over 2 g of monosodium phosphate and 120 ml ofwater+ice, extraction is carried out with ether, the extracts are washedwith a saturated solution of sodium chloride and dried. Afterpurification on silica eluting with methylene chloride-acetone: 96-4,approx. 5 g of expected product (foam) is obtained.

ANALYSES:

    ______________________________________                                        IR (CHCl.sub.3) cm.sup.-1                                                     ______________________________________                                        Absence of          O═C--NH                                                 C.tbd.N 2238                                                                  >C═O 1790-1735                                                            Aromatics 1615-1576-1505                                                    ______________________________________                                    

STAGE 2: 5,5-bis(hydroxymethyl)-3-(4-cyano-3-(trifluoromethyl)phenyl)-2,4-dioxo-1-imidazolidineacetonitrile

4.68 g of the product obtained in Stage 1 above in solution in 50 ml ofmethanol and 8.8 ml of hydrochloric acid are introduced and the whole istaken to reflux for 30 minutes. 60 ml of ice-cooled water is added,extraction is carried out with ether, the ethereal phase is washed witha saturated solution of sodium chloride and dried. After purification onsilica, eluting with methylene chloride-acetone: 85-15 then 8-2, thecrystals obtained are taken up in 10 ml of methylene chloride, separatedout and dried. In this way 2.26 g of expected product (white crystals)is obtained. M.p.=157-158° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 48.92 49.0                                                                  H  3.01  2.8                                                                  F 15.48 15.6                                                                  N 15.21 15.2                                                                ______________________________________                                        I.R. Nujol (cm.sup.-1)                                                          Absorption OH/NH 3582                                                                            -3455                                                      C.tbd.N 2240                                                                  >C═O 1782-1726                                                            Aromatics 1610-1574-1504                                                    ______________________________________                                    

STAGE 3: 5,5-bis(fluoromethyl)-3-(4-cyano-3-(trifluoromethyl)phenyl)-2,4-dioxo-1-imidazolidineacetonitrile

1 ml of tetrahydrofuran is introduced, cooled down to -50° C. and 0.66ml of DAST then 0.368 g of the product obtained in Stage 2 above insolution in 5 ml of anhydrous tetrahydrofuran are added and rinsing iscarried out with 0.5 ml of tetrahydrofuran. The reaction medium isallowed to return to ambient temperature then maintained for 30 minutesat 30° C. It is poured slowly into 30 ml of sodium hydrogen carbonate,followed by ice-cooling, extraction is carried out with ether, theextracts are washed with a saturated solution of sodium chloride anddried. After purification on silica, eluting with methylene chloride,0.321 g of expected product (white crystals) is obtained. M.p.=125° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 48.40 48.3                                                                  H  2.44  2.3                                                                  F 25.52 25.2                                                                  N 15.05 15.1                                                                ______________________________________                                        I.R. Nujol (cm.sup.-1)                                                          C.tbd.N 2238                                                                  >C═O 1788-1736                                                            Aromatics 1616-1578-1508                                                    ______________________________________                                    

EXAMPLE 34-(2,5-dioxo-4,4-bis(fluoromethyl)-3-ethyl-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

STAGE 1:4-(4,4-bis(hydroxymethyl)-2,5-dioxo-3-ethyl-1-imida-zolidinyl)-2-(trifluoromethyl)-benzonitrile

The operation is carried out as in a) and b) of Stage 6 of Example 1starting with 110 mg of 50% sodium hydride, 1 g of the product obtainedin Stage 5 of Example 1, 5 ml of dimethylformamide and 0.24 ml of ethyliodide. In this way 1.1 g of product is obtained which is taken up in0.2 ml of methanol and 4 ml of hydrochloric acid (2N). In this way 608mg of expected product (white crystals) is obtained.

M.p.=155-156° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 50.42 50.5                                                                  H  3.95  3.9                                                                  F 15.95 15.6                                                                  N 11.76 11.6                                                                ______________________________________                                        I.R. Nujol (cm.sup.-1)                                                              Absorption OH/NH approx.                                                                         3330                                                   C.tbd.N 2238                                                                  C═O 1784-1722                                                             Aromatics 1620-1580-1510                                                    ______________________________________                                    

STAGE 2:4-(2,5-dioxo-4,4-bis(fluoromethyl)-3-ethyl-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

The operation is carried out as in Stage 7 of Example 1, starting with 1ml of tetrahydrofuran, 0.66 ml of diethylaminotrifluorosulphide and 349mg of the product obtained in Stage 1 above in 4 ml of tetrahydrofuran.In this way 319 mg of expected product (white crystals) is obtained.M.p.=129-130° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 49.89 50.0                                                                  H 3.35 3.2                                                                    F 26.29 25.95                                                                 N 11.63 11.6                                                                ______________________________________                                        I.R. CHCl.sub.3 (cm 1)                                                          C.tbd.N 2238                                                                  > = O 1787-1734                                                               Aromatics 1615-1578-1505                                                    ______________________________________                                    

EXAMPLE 4 4-(4,4-bis(fluoromethyl)2,5-dioxo-3-(1-methylethyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

STAGE 1:4-(4,4-bis(hydroxymethyl)-2,5-dioxo-3-(1-methylethyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

The operation is carried out as in a) and b) of Stage 6 of Example 1starting with 110 mg of 50% sodium hydride, 1 g of the product obtainedin Stage 5 of Example 1, 5.5 ml of dimethylsulphoxide and 0.3 ml ofisopropyl iodide. 1.1 g of product is obtained which is taken up in 12ml of methanol and 4 ml of 2N hydrochloric acid. In this way 574 mg ofexpected product (white crystals) is obtained. M.p.=172-173° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 51.75 51.9                                                                  H  4.34  4.1                                                                  F 15.35 15.2                                                                  N 11.32 11.2                                                                ______________________________________                                        I.R. nujol (cm.sup.-1)                                                          OH/NH 3390                                                                    C.tbd.N 2240                                                                  > = O 1782-1720                                                               Aromatics 1618-1575-1508                                                    ______________________________________                                    

STAGE 2:4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(1-methylethyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

The operation is carried out as in Stage 7 of Example 1, starting with 1ml of tetrahydrofuran, 0.66 ml of diethylaminotrifluorosulphide and 316mg of the product obtained in Stage 1 above in 4 ml of tetrahydrofuran.In this way 298 mg of expected product (white crystals) is obtained.M.p.=153-154° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 51.21 51.1                                                                  H  3.76  3.6                                                                  F 25.01 24.9                                                                  N 11.20 11.3                                                                ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                     C.tbd.N 2238                                                                  C═O 1787-1734                                                             Aromatics 1616-1578-1505                                                    ______________________________________                                    

EXAMPLE 54-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(2-propynyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

STAGE 1: 4-(4,4-bis(hydroxymethyl)-2,5-dioxo-3-(2-propynyl)1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

The operation is carried out as in a) and b) of Stage 6 of Example 1starting with 420 mg of 50% sodium hydride, 3.86 g of the productobtained in Stage 5 of Example 1, 15 ml of dimethylformamide and 1.30 gof propargyl bromide, in 2 ml of dimethylformamide. 3.872 g of productis obtained which is taken up in 18 ml of methanol and 6 ml of 2Nhydrochloric acid. In this way 993 mg of expected product (whitecrystals) is obtained. M.p.=125-126° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 52.32 52.4                                                                  H  3.29  3.2                                                                  F 15.52 15.5                                                                  N 11.44 11.4                                                                ______________________________________                                        I.R. nujol (cm.sup.-1)                                                          OH/NH 3495-3360                                                               C.tbd.CH 3308                                                                 C.tbd.N 2236                                                                  C═O 1784-1730                                                             Aromatics 1666-1576-1506                                                    ______________________________________                                    

STAGE 2: 4-[4,4-bis[[[(trifluoromethyl)sulphonyl]oxy]methyl]2,5-dioxo-3-(2-propynyl)-1-imidazolidinyl]-2-(trifluoromethyl)-benzonitril

500 mg of product obtained in Stage 1 above, 8 ml of methylene chloride,1.2 ml of pyridine and 61 mg of 4-dimethylaminopyridine are introduced,the whole is taken to about -10° C., 1 ml of triflic anhydride is addedand the reaction medium is left to react at 0° C. for about 45 minutes.It is then poured into 20 ml of sodium bicarbonate, extraction iscarried out 3 times with ethyl acetate, the extracts are washed withsalt water and dried. In this way 982 mg of expected product (inertfriable foam) is obtained.

STAGE 3: 4-(4,4-bis(fluoromethyl) 2,5-dioxo-3-(2-propynyl)1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

982 mg of the crude product obtained in Stage 2 above and 8 ml oftetrahydrofuran are introduced and a 1.1 M solution in tetrahydrofuranof 3 ml of tetrabutylammonium fluoride is added over about 5 minutes.After 30 minutes, the reaction medium is poured into 25 ml of 50% sodiumbicarbonate, extraction is carried out 3 times with methylene chloride,the extracts are washed with water and dried. A first purification iscarried out on silica eluting with methylene chloride-acetone: 99-1,then a second purification is carried out on silica eluting withcyclohexane-ethyl acetate: 7-3. In this way, after evaporation of thefractions and trituration in ether, 252 mg of expected product (whitecrystals) is obtained. M.p.=126-127° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 51.76 52.0                                                                  H  2.71  2.7                                                                  F 25.58 25.3                                                                  N 11.32 11.1                                                                ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                     .tbd.CH 3307                                                                  C.tbd.N 2238                                                                  C═O 1792-1738                                                             Aromatics 1615-1575-1505                                                    ______________________________________                                    

EXAMPLE 64-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(4-hydroxy-2-butyn-1-yl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

STAGE 1:4-[3-[4-(acetyloxy)-2-butyn-1-yl]-4,4-bis[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)-benzonitrile

416 mg of 50% sodium hydride and dropwise 4 g of the product obtained inStage 5 of Example 1 and 15 ml of dimethylformamide are introduced andthe resultant mixture is rinsed with 1 ml of dimethylformamide. 10minutes after the end of the release of hydrogen, 3.2 g of4-bromo-2-butyne-1-ol acetate prepared as described in J. W. Lown GENE149, 81 (1994) and 2 ml of dimethylformamide are added, and rinsing iscarried out with 0.5 ml of dimethylformamide. After one hour 30 minutes,the reaction medium is poured into 100 ml of water containing 0.5 g ofmonopotassium phosphate, extraction is carried out 4 times with ether,the organic phase is washed with water and with salt water and dried.Purification is carried out by chromatography on silica eluting withmethylene chloride-acetone: 95-5 and 4.47 g of expected product (orangeresin) is obtained.

ANALYSES:

    ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                   ______________________________________                                        C.tbd.N             2236                                                        > = O 1735-1729                                                               Aromatics 1616-1575-1505                                                    ______________________________________                                    

STAGE 2:4-[3-[4-(acetoxy)-2-butyn-1-yl]-4,4-bis[[(hydroxymethyl]-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)-benzonitrile

4.4 g of the product obtained in Stage 1 above, 14 ml oftetrahydrofuran, 28 ml of acetic acid and 7 ml of water are introducedand the whole is heated to 60° C.±5° C. for 4 hours. The acetic acid isevaporated off, 100 ml of ethyl acetate is added, followed by washingwith bicarbonate and drying. After chromatography on silica eluting withmethylene chloride-acetone: 85-15, 1.99 g of expected product (whitefoam) is obtained.

ANALYSES:

    ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                   ______________________________________                                        OH                  3618-3548                                                   C.tbd.N 2235                                                                  > = O 1784-1729                                                               Aromatics 1617-1607-1572-1505                                               ______________________________________                                    

STAGE 3:4-[3-[4-(acetoxy)-2-butyn-1-yl]-4,4-bis(fluoromethyl)-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)-benzonitrile

The operation is carried out as in Stages 2 and 3 of Example 5, startingwith 439 mg of the product obtained in Stage 2 above, 6 ml of methylenechloride, 1.35 ml of 2,6-lutidine, 50 mg of 4-dimethylaminopyridine and1 ml of trifluoromethane sulphonic anhydride is added at a temperatureof 0 to 5° C. The reaction medium is left to react for one hour at thistemperature then poured into a mixture of 50 ml of sodiumbicarbonate-ethyl acetate: 1--1, followed by decanting, washing withsalt water and drying. Then the product is taken up in 6 ml oftetrahydrofuran, and a 1.1 M solution of 2.3 ml of tetrabutylammoniumfluoride in tetrahydrofuran is added. The medium is poured into 60 ml ofsodium bicarbonate-ethyl acetate: 1--1, followed by decanting, washingwith salt water and drying. After purification by chromatography onsilica eluting with methylene chloride-ethyl acetate: 95-5, 177 mg ofexpected product (resin) is obtained.

ANALYSES:

    ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                   ______________________________________                                        C.tbd.N             2238                                                        > = O 1792-1757                                                               Aromatics 1615-1575-1505                                                    ______________________________________                                    

STAGE 4:4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(4-hydroxy-2-butyn-1-yl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

1 g of the product obtained in Stage 3 above, 18 ml of methanol and 4.5ml of 2N hydrochloric acid are introduced then left for one hour 30minutes at 50° C. The reaction medium is then returned to ambienttemperature, poured into 30 ml of sodium bicarbonate, extraction iscarried out with ethyl acetate 3 times, the extracts are washed withsalt water and dried. After chromatography on silica eluting withmethylene chloride-acetone: 85-15, 780 mg of expected product (whitecrystals) is obtained. M.p.=131-132° C.

ANALYSES:

    ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                   ______________________________________                                        OH                  3610                                                        C.tbd.N 2238                                                                  > = O 1792-1736                                                               Aromatics 1615-1576-1505                                                    ______________________________________                                    

EXAMPLE 74-(4,4-bis(fluoromethyl)-2,5-dioxo-3-methyl-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

1 ml of tetrahydrofuran is introduced, taken to -30° C., 3.24 ml ofdiethylaminotrifluorosulphide, then 0.12 g of the product of Example 24of FR 2715402 are added and the whole is rinsed with 0.5 ml oftetrahydrofuran, then left to rise to ambient temperature and taken to+30° C. After 40 minutes, the reaction medium is poured over 5 g of icein 20 ml of sodium bicarbonate, extraction is carried out 5 times withmethylene chloride, the organic phase is washed with salt water anddried. Purification is carried out by chromatography on silica elutingwith methylene chloride-ethyl acetate: 99-1 and in this way 111 mg ofexpected product (white crystals) is obtained. M.p.=137-138° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 48.42 48.2                                                                  H  2.90  2.8                                                                  F 27.35 26.9                                                                  N 12.10 11.9                                                                ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                     C.tbd.N 2235                                                                  > = O 1790-1735                                                               Aromatics 1617-1580-1505                                                    ______________________________________                                    

EXAMPLE 84-(3-(4-hydroxy-2-butyn-1-yl)-4,4-dimethyl-2,5-dione-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

a) Condensation of the 4-tertbutyldimethylsiloxy-2-butyne chain

103 mg of 50% sodium hydride is introduced, 570 mg of the product ofExample 8 of EP 0494819, 3.5 ml of dimethylformamide are added and thewhole is rinsed with 0.5 ml of dimethylformamide. 20 minutes after therelease of hydrogen has stopped, 0.5 g of1-bromo-4-tertbutyldimethylsiloxy-2-butyne prepared as indicated in J.W. Lown et al. GENE 149, 81 (1994) is added and the reaction medium istaken to ₄₀ ° C. After 50 minutes, it is poured into 40 ml of watercontaining about 0.5 g of monopotassium phosphate, extraction is carriedout 4 times with ether, the organic phase is washed with water then withsalt water and dried. Purification is carried out by chromatography onsilica eluting with methylene chloride-acetone: 98-2 and 732 mg of palesyrup is obtained.

b) Hydrolysis of the silylated ether

The 732 mg of product obtained in a) above is taken up in 7.5 ml ofmethanol and 1.5 ml of 2N hydrochloric acid. After 40 minutes, thereaction medium is poured into 30 ml of 50% sodium bicarbonate,extraction is carried out 3 times with ethyl acetate, the extracts arewashed with salt water and dried. After purification by chromatographyon silica eluting with methylene chloride-acetone: 92.5-7.5, 516 mg ofexpected product (white crystals) is obtained. M.p.=125-126° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 55.89 56.0                                                                  H  3.86  3.8                                                                  F 15.60 15.9                                                                  N 11.50 11.7                                                                ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                     OH 3608                                                                       C.tbd.N 2230                                                                  > = O 1783-1726                                                               Aromatics 1616-1575-1505                                                    ______________________________________                                    

EXAMPLE 94-[2,4-dioxo-1-(4-hydroxybutyl)-1,3-diazaspiro-[4.5]decan-3-yl]-2-(trifluoromethyl)-benzonitrile

STAGE 1: 1-amino-cyclohexanecarbonitrile

1.23 g of sodium cyanide, 1.58 g of ammonium chloride and 8 ml ofammonium hydroxide are introduced, the whole is taken to 0° C. and 2.1 gof cyclohexanone is added. The reaction medium is left to return toambient temperature under agitation for 18 hours, diluted in a smallamount of water and decanted. The aqueous phase is extracted withmethylene chloride, the organic phases are combined, washed with saltwater, dried, filtered and concentrated. In this way 2.38 g of expectedproduct (colourless oil) is obtained.

ANALYSES:

    ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                   ______________________________________                                        NH.sub.2             3380-3315                                                  CN 2225                                                                     ______________________________________                                    

STAGE 2:4-[2-imino-4-oxo-1,3-diazaspiro[4.5]decan-3-yl]-2-(trifluoromethyl)-benzonitrile

3.75 ml of an 18% 1,2-dichloroethane solution of the product ofPreparation 1 is introduced, 10 ml of dry dichloroethane and 0.22 ml oftriethylamine are added, the whole is taken to -30° C., 558 mg of theproduct obtained in Stage 1 above in 2 ml of dichloroethane is added andthe reaction medium is left at ambient temperature for 18 hours. Afterchromatography on silica eluting with methylene chloride-acetone: 8-2,1.10 g of expected product (white solid) is obtained.

ANALYSES:

    ______________________________________                                        I.R. (cm.sup.-1)                                                              ______________________________________                                        OH/NH           3370-3290                                                       CN 2240                                                                       C═O 1743                                                                  C═N 1678                                                                  Aromatics 1615-1606-1572-1542-1508                                          ______________________________________                                    

STAGE 3:4-(2,4-dioxo-1,3-diazaspiro(4.5)decan-3-yl)-2-(trifluoromethyl)-benzonitrile

1.10 g of the product obtained in Stage 2 above, 3 ml of 6N hydrochloricacid and 8 ml of ethanol are introduced, the mixture is taken to refluxfor one hour, cooled down to ambient temperature, neutralized by theaddition of sodium hydrogen carbonate, extracted with ethyl acetate. Theorganic phases are combined, washed with water, dried, filtered andconcentrated. After chromatography on silica eluting with methylenechloride-acetone: 9-1, then recrystallization from isopropanol, 470 mgof expected product (white solid) is obtained. M.p.=187° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 57.0 56.8                                                                   H 4.15 4.0                                                                    N 12.50 12.5                                                                  F 16.9 16.8                                                                 ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                     NH 3450                                                                       CN 2235                                                                       C═O 1787-1727                                                             Aromatics 1617-1575-1505                                                    ______________________________________                                    

STAGE 4:4-[2,4-dioxo-1-(4-hydroxybutyl)-1,3-diazaspiro-[4.5]decan-3-yl]-2-(trifluoromethyl)-benzonitrile

28 mg of 50% sodium hydride and 3 ml of dimethylformamide areintroduced, agitation is carried out at ambient temperature for 5minutes, 170 mg of the product obtained in Stage 3 above is added andthe whole is left under agitation for 20 minutes until the release ofhydrogen has stopped. 202 mg of O-trimethylsilyl-4-iodo-n-butanol isthen added and the reaction medium is left under agitation for 2 hours.After hydrolysis using saturated ammonium chloride, extraction iscarried out with ethyl acetate. The organic phases are combined, washedwith water, dried, filtered and concentrated. The residue is solubilizedin 10 ml of methanol and 0.5 ml of 2N hydrochloric acid is added. Afteragitation for 5 minutes, the solution is neutralized by the addition ofsaturated sodium hydrogen carbonate and extraction is carried out withethyl acetate. The organic phases are combined, dried, filtered andconcentrated. After chromatography on silica eluting with methylenechloride-acetone: 9-1, 158 mg of expected product (white solid) isobtained. M.p.=145° C.

ANALYSES:

    ______________________________________                                        M.A.           % calculated                                                                            found                                                ______________________________________                                          C 58.8 58.8                                                                   H  5.4  5.2                                                                   F 13.9 13.6                                                                   N 10.3 10.1                                                                 ______________________________________                                        I.R. CHCl.sub.3 (cm.sup.-1)                                                     OH 3626                                                                       CN 2236                                                                       C═O 1772-1719                                                             Aromatics 1615-1575-1505.                                                   ______________________________________                                    

EXAMPLE 10

Tablets were prepared having the following composition:

Product of Example 6 . . . 100 mg

Excipient s.q. for a tablet completed at . . . 300 mg (Detail of theexcipient: lactose, starch, talc, magnesium stearate).

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

1) Study of the Affinity of the Products of the Invention for theAndrogen Receptor

Male Sprague Dawley EOPS rats weighing 180-200 g, castrated 24 hourspreviously, are sacrificed, the prostates are removed, weighed andhomogenized at 0° C. using a Potter glass flask, in a buffered solution(10 mM Tris, 0.25M saccharose, 0.1 mM PMSF(phenylmethanesulphonylfluoride), 20 mM sodium molybdate, HCl pH 7.4; towhich 2 mM of DTT (DL dithiothreitol) is added extemporaneously), at therate of 1 g of tissue per 8 ml of buffer.

The homogenate is then ultracentrifuged at 0° C. for 30 minutes at209,000 g. Aliquots of the supernatant obtained (=cytosol), areincubated for 30 minutes and 24 hours at 0° C., with a constantconcentration (T) of tritiated testosterone and in the presence ofincreasing concentrations (0 to 2500×10⁻⁹ M), either of unlabelledtestosterone, or of the products to be tested. The concentration ofbound tritiated testosterone (B) is then measured in each incubate bythe method of adsorption with carbon dextran.

Calculation of the Relative Bond Affinity (RBA).

The following 2 curves are drawn: the percentage of bound tritiatedhormone B/T as a function of the logarithm of the concentration ofunlabelled reference hormone and B/T as a function of the logarithm ofthe concentration of unlabelled product tested. The straight line of theequation I₅₀ =(B/Tmax+B/Tmin)/2 is determined.

B/Tmax=% of bound tritiated hormone for an incubation of this tritiatedhormone at the concentration (T).

B/Tmin=% of bound tritiated hormone for an incubation of this tritiatedhormone at the concentration (T) in the presence of a large excess ofunlabelled hormone (2500×10⁻⁹ M).

The intersections of the straight line I₅₀ and the curves allow theevaluation of the concentrations of the unlabelled reference hormone(CH) and of the tested unlabelled product (CX) which inhibit by 50% thebinding of the tritiated hormone on the receptor. The relative bondaffinity (RBA) of the tested product is determined by the equationRBA=100 (CH)/(CX).

The following results are obtained, expressed in RBA.

Reference product (Testosterone): 100

                  TABLE 1                                                         ______________________________________                                        Product of example                                                                          RBA: Incubation 24 hours                                        ______________________________________                                        1             42                                                                3 43                                                                        ______________________________________                                    

2) Determination of the Reducing Effect on the Costo-vertebral Gland ofthe Hamster

The local activity (topical) of an antiandrogen is determined by thereduction which it brings about in the surface area of thecostovertebral gland of the hamster (hereafter C.V.G.), anandrogen-dependent organ situated on the flanks of the animal.

The animals are male hamsters weighing about 140 g, 14 weeks old andoriginating from the Charles River breed (USA), they are subjected to along photoperiod (16 hours of light, 8 hours of darkness). The animalsare treated every day, except for the weekend, for 3 weeks (14administrations). The product to be tested is applied, by topical route,on the right-hand C.V.G., the left-hand one serving as the control. Thesurface of the gland has been shaved beforehand. The animals aresacrificed by bleeding the carotid artery 24 hours after the lasttreatment. The C.V.G.'s are removed, measured and weighed. The localactivity of a product is determined by the % of reduction in the surfacearea of the C.V.G. which it induces in comparison with the 1st day ofthe experiment and compared to the animals treated with solvent only.

                  TABLE 2                                                         ______________________________________                                                       % CVG reduction with                                             Product of example 3 μg/jour                                             ______________________________________                                        1              -32                                                              3 -33                                                                         9 -25                                                                       ______________________________________                                    

3) Determination of the Reducing Effect of the Weight of the Prostate inan Intact Male Rat

The systemic activity of an antiandrogen is determined by the reductionin the weight of the prostate which it brings about in an intact animal.

The animals used are male rats of the Sprague Dawley strain weighingabout 200 g, 7 weeks old, originating from the Iffa Credo breed(France). The experiment is carried out over two weeks, except for theweekend.

The product can be administered by oral, sub-cutaneous or percutaneousroute.

The solvents used are then: by oral route: 0.5% aqueous solution ofmethylcellulose under a volume of 5 ml/kg, by sub-cutaneous route:wheatgerm oil in 10% ethanol under a volume of 0.2 ml/kg, and bypercutaneous route: ethanol under a volume of 50 ul on previously-shavedskin.

The treatment is carried out from day 0 to day 4 then (after theweekend) from day 7 to day 10. The animals are sacrificed the day afterthe last treatment by bleeding the carotid artery, the prostates areremoved and fixed in demineralized water containing 10% formol for 72hours. They are then dissected and weighed. The blood is removed inorder to determine, by radioimmunological assay, the amount of serictestosterone. The antiandrogen activity of the product is expressed as %reduction in the weight of the prostates and as % variation in theamounts of testosterone compared to the animals treated by the solventonly.

                  TABLE 3                                                         ______________________________________                                                      % reduction in the prostate                                       Product of example weight with 3 mg/kg P.O.                                 ______________________________________                                        1             -27                                                               3 -20                                                                         8 -35                                                                       ______________________________________                                    

What is claimed is:
 1. A compound selected from the group consisting of4-(4,4-bis(fluoromethyl)-2,5-dioxo-3-(4-hydroxy-2-butyn-1-yl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,4-(3-(4-hydroxy-2-butyn-1-yl)-4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,4-[2,4-dioxo-1-(4-hydroxybutyl)-1,3-diazaspiro[4,5]decan-3-yl]-2-(trifluoromethyl)-benzonitrileand the addition salts with non-toxic, pharmaceutically acids.
 2. Anantiandrogenic composition comprising an antiandrogenically effectiveamount of a compound of claim 1 and an inert pharmaceutical carrier. 3.A method of inducing antiandrogenic activity in warm-blooded animalscomprising administering to warm-blooded animals an antiandrogenicallyeffective amount of a compound of claim 1.